- 作者: Kay L.H. Wu, Chen-Hsiu Chen and Cheng-Dean Shih
- 作者服務機構: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang- Gung Memorial Hospital, Kaohsiung, Taiwan
- 中文摘要: --
- 英文摘要:
Background: Estrogen acts on the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, to elicit vasodepressor effects via an estrogen receptor (ER)?-dependent mechanism. We investigated in the present study nontranscriptional mechanism on cardiovascular effects following activation of ER? in the RVLM, and delineated the involvement of phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (Akt) signaling pathway in the effects.
Methods: In male Sprague-Dawley rats maintained under propofol anesthesia, changes in arterial pressure, heart rate and sympathetic neurogenic vasomotor tone were examined after microinjection bilaterally into RVLM of 17?-estradiol (E2?) or a selective ERa or ER? agonist. Involvement of ER subtypes and PI3K/Akt signaling pathway in the induced cardiovascular effects were studied using pharmacological tools of antagonists or inhibitors, gene manipulation with antisense oligonucleotide (ASON) or adenovirus-mediated gene transfection.
Results: Similar to E2? (1 pmol), microinjection of ER? agonist, diarylpropionitrile (DPN, 1, 2 or 5 pmol), into bilateral RVLM evoked dose-dependent hypotension and reduction in sympathetic neurogenic vasomotor tone. These vasodepressive effects of DPN (2 pmol) were inhibited by ER? antagonist, R,R-tetrahydrochrysene (50 pmol), ASON against ER? mRNA (250 pmol), PI3K inhibitor LY294002 (5 pmol), or Akt inhibitor (250 pmol), but not by ERa inhibitor, methyl-piperidino-pyrazole (1 nmol), or transcription inhibitor, actinomycin D (5 or 10 nmol). Gene transfer by microinjection into bilateral RVLM of adenovirus encoding phosphatase and tensin homologues deleted on chromosome 10 (5???108 pfu) reversed the vasodepressive effects of DPN.
Conclusions: Our results indicate that vasodepressive effects following activation of ER? in RVLM are mediated by nongenomic activation of PI3K/Akt signaling pathway. This study provides new insight in the intracellular signaling cascades involved in central vasodepressive functions of estrogen. - 中文關鍵字: --
- 英文關鍵字: 17β-estradiol, Estrogen receptor, Rostral ventrolateral medulla, Systemic arterial pressure, PI3K/Akt signaling pathway